Glutamate is the major excitatory neurotransmitter in cerebral cortex. Electrophysiology and pharmacology have distinguished several types of glutamate receptors, but only with the advent of modern molecular techniques has their full diversity been recognized. Given the central role of glutamate in excitatory neurotransmission, understanding its receptors is of fundamental significance to neuroscience. It may also have practical implications: Drugs acting on glutamergic systems have not yet had a major impact on clinical practice, presumably because the transmitter is so ubiquitous that the selectivity of these agents is limited. Rational design based on a better understanding of receptor subtypes may yield a new generation of drugs with greater specificity of action. Novel research on the synaptic localization of glutamate receptor subunits in dentate gyrus and somatic sensory cortex is proposed, utilizing a new postembedding gold immunocytochemical technique for electron microscopic localization. This will allow us to investigate the subcellular distribution of glutamate receptors and their relationship to the plasma membrane and the active zone, as well as to assess how faithfully light microscopy reflects the underlying distribution of receptors. To explore how the arrangement of glutamate receptors may influence calcium entry into neurons, we will study the pattern of colocalization of AMPA subunits, and the distribution of AMPA and NMDA receptors on spines and dendritic shafts. The information thus gathered will allow study of the dynamics of glutamate receptors. The third part of the proposed research will test whether there are changes in distribution, concentration, or expression of these receptors associated with altered synaptic efficacy in two models of cortical plasticity: responsiveness in the barrel field of somatic sensory cortex after modification of its input, and long-term potentiation in the perforant pathway from entorhinal cortex to dentate gyrus. A deeper knowledge of mechanisms that may underlie cortical plasticity is of potential significance in understanding the reorganization associated with recovery from brain injury.